The proposed research is intended to investigate the potential for pulsed HIFU to enhance drug penetration into the interstitium of tumors. This has particular applications to hepatocellular carcinoma (HCC), where localized therapy has demonstrated benefit;however, local recurrence is common. Ultrasound enhanced drug delivery can potentially be used in conjunction with TACE to improve local response and control. These studies are designed to provide additional insight into the acoustic mechanisms involved in ultrasound enhanced (cavitation, microstreaming, streaming). The concept of ultrasound enhanced drug delivery is extremely complex. It is highly likely that several mechanisms are involved and different ultrasound parameters will be needed to harness these effects. For example, it has been demonstrated that intravascular cavitation will increase capillary permeability in normal capillaries. Intravascular cavitation also appears to enhance permeability in capillaries of tumors permitting larger molecules, such as nanoparticles, to traverse the vascular barrier in greater concentrations. However, once these drug-loaded nanoparticles enter the interstitium, their penetration is limited by their size and diffusion. What has yet to be demonstrated is whether ultrasound can enhance the penetration of these molecules into the interstitum to exert effect on viable tumor cells that are not located adjacent to a vessel and the mechanisms involved. In addition, there is the possibility of ultrasound enhancing penetration of drug directly into the cell. The intent of this R03 grant is to obtain additional supporting data that could be used to support an R01 application to further investigate the role of ultrasound in enhancing the delivery of drug. In future studies, I intend to investigate the use of pulsed HIFU to enhance vascular permeability, followed by enhanced penetration. In addition, I have developed collaborations with other investigators who are developing novel nanoparticle vehicles for drugs that could be used in conjunction with ultrasound for targeted drug delivery. PUBLIC HEALTH RELEVANCE: The overall aim of this study is to investigate the use of pulsed HIFU for enhancing the penetration of a chemotherapeutic agent into the interstitium of tumors and to investigate the potential mechanisms involved. If effective, pulsed HIFU potentially could be used in conjunction with novel drug delivery vehicles (e.g., drug eluting beads or nanoparticles) to deliver newer chemotherapeutic agents for more effective treatment of localized HCC while limiting systemic toxicity. The overall hypothesis of this research is that pulsed HIFU can enhance penetration of small molecules into the interstitium of tumors such as hepatocellular carcinoma.